Proteinopathies, diseases of protein misfolding and aggregation, are debilitating age-related diseases such as ALS, Alzheimer's, Parkinson's and Huntington's Diseases, for which there are currently no interventions to reduce cell dysfunction and death. Harnessing the cell's own protective responses to protein misfolding such as the heat shock response (HSR) dramatically ameliorates the toxic effects of protein aggregation in all animal models of proteinopathies. Recent studies have shown that the HSR of individual cells of an organism is under non-autonomous control of the nervous system. The objective of this proposal is to determine precisely how neurons control the HSR in another cell. We have identified a crucial element of this cytoprotective mechanism: thermosensory-induced serotonin (5-hydroxytryptamine, 5-HT) release is necessary and sufficient to induce the HSR in other cells and thereby suppress protein aggregation and misfolding. We show this by live imaging of HSF-1, the transcription factor responsible for the expression of protective heat shock protein (HSP) genes, in combination with optogenetic excitation of specific neurons in intact animals. Using techniques developed in our laboratory, we will investigate the inter-tissue signaling mechanisms by which sensory stress perception results in cytoprotection. The innovation of the proposed work is that it will elucidate, in-depth, for the first time, a mechanism of cell non-autonomous control of the HSR. Aging results in the inevitable decline in an organism's ability to withstand stress. It is unclear whether decreases in the efficiency of stress signaling mechanisms themselves contribute to this aging-dependent impairment of stress responses. Our expertise in dissecting the mechanisms by which the neurosensory system signals stress to distal tissues, and non-autonomously controls their response allows us a unique opportunity to address this question. Hypothesis: Thermosensory-induced release of 5-HT activates adaptive cellular stress responses that protect protein homeostasis. Aim 1. How do thermosensory (AFD) neurons elicit 5-HT release from serotonergic neurons? Aim 2. What inter-tissue stress signaling pathways are activated by 5-HT in responsive cells?